Proximal Dominant Hereditary Motor and Sensory Neuropathy With Proximal Dominance Association With Mutation in the TRK-Fused Gene
Proximal Dominant Hereditary Motor and Sensory Neuropathy With Proximal Dominance Association With Mutation in the TRK-Fused Gene
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DOI：
10.1001/jamaneurol.2013.1250
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发表时间：
2013-05-01
期刊：
影响因子：
29
通讯作者：
Choi, Byung-Ok
中科院分区：
文献类型：
--
作者：
Lee, Sang-Soo;Lee, Hye Jin;Choi, Byung-Ok
重要性：遗传性运动和感觉神经病变伴近端显性（HMSN-P）是一种罕见的常染色体显性成人发病的腓骨肌萎缩症。自1997年以来，仅在日本后代中发现了hsnp，尚未发现致病基因。目的：探讨韩国某家族hsnp的遗传原因及致病机制。设计：遗传和观察分析。单位：罕见神经疾病转化研究中心。参与者：来自一个患有HMSN-P的韩国家庭的28个人（12男16女）。主要观察指标：全外显子组测序、连锁分析和磁共振成像。结果：通过全外显子组测序，我们发现HMSN-P是由trk融合基因（TFG）突变引起的。韩、日两国患者HMSN-P表现出临床异质性。与日本患者相比，本组患者病情进展更快，腓肠神经感觉神经动作电位在疾病早期丧失。此外，震颤和高脂血症也经常出现。下肢的磁共振成像显示明显的近端占主导地位和连续的肌肉受累模式，与1A型腓骨肌萎缩症患者的模式明显不同。特别是，神经内膜血管显示管腔明显变窄，囊性内皮细胞肿胀。结论及意义：HMSN-P的根本原因是位于3q13.2染色体上的TFG突变。这种疾病并不局限于日本后裔，在本研究中注意到明显的神经内膜血管狭窄。我们认为TFG可以影响周围神经组织。
Importance: Hereditary motor and sensory neuropathy with proximal dominance (HMSN-P) has been reported as a rare type of autosomal dominant adult-onset Charcot-Marie-Tooth disease. HMSN-P has been described only in Japanese descendants since 1997, and the causative gene has not been found.Objectives: To identify the genetic cause of HMSN-P in a Korean family and determine the pathogenic mechanism.Design: Genetic and observational analysis.Setting: Translational research center for rare neurologic disease.Participants: Twenty-eight individuals (12 men and 16 women) from a Korean family with HMSN-P.Main Outcome Measures: Whole-exome sequencing, linkage analysis, and magnetic resonance imaging.Results: Through whole-exome sequencing, we revealed that HMSN-P is caused by a mutation in the TRK-fused gene (TFG). Clinical heterogeneities were revealed in HMSN-P between Korean and Japanese patients. The patients in the present report showed faster progression of the disease compared with the Japanese patients, and sensory nerve action potentials of the sural nerve were lost in the early stages of the disease. Moreover, tremor and hyperlipidemia were frequently found. Magnetic resonance imaging of the lower extremity revealed a distinct proximal dominant and sequential pattern of muscular involvement with a clearly different pattern than patients with Charcot-Marie-Tooth disease type 1A. Particularly, endoneural blood vessels revealed marked narrowing of the lumen with swollen vesicular endothelial cells.Conclusions and Relevance: The underlying cause of HMSN-P proves to be a mutation in TFG that lies on chromosome 3q13.2. This disease is not limited to Japanese descendants, and marked narrowing of endoneural blood vessels was noted in the present study. We believe that TFG can affect the peripheral nerve tissue.